(12) United States Patent
`Krause et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,916,158 B2
`*Dec. 23, 2014
`
`USOO8916158B2
`
`(54) FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-(x ASSOCIATED
`DISORDERS
`
`(71) Applicant: Abeie Biotechnology Ltd, Hamilton
`(BM)
`
`(72) Inventors: Hans-Juergen Krause, Gruenstadt
`(DE); Lisa Baust, Ludwigshafen (DE);
`Michael Dickes, Rodersheim-Gronau
`(DE)
`
`(73) Assignee: Abeie Biotechnology Ltd., Hamilton
`(BM)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is subject to a terminal dis
`claimer.
`
`(21) Appl.No.: 14/453,490
`
`(22) Filed:
`
`Aug. 6, 2014
`
`(65)
`
`Prior Publication Data
`
`Nov. 20,2014
`US 2014/0341925 A1
`Related US. Application Data
`
`(63) Continuation of application No. 14/322,581, ?led on
`Jul. 2, 2014, which is a continuation of application No.
`14/091,938, ?led on Nov. 27, 2013, now Pat. No.
`8,795,670, which is a continuation of application No.
`13/471,820, ?led on May 15, 2012, which is a
`continuation of application No. 10/525,292, ?led as
`application No. PCT/IB03/04502 on Aug. 15, 2003,
`now Pat. No. 8,216,583, which is a continuation of
`application No. 10/222,140, ?led on Aug. 16, 2002,
`now abandoned.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A61K 39/395
`C07K 16/00
`C07K 16/22
`00 7K 14/525
`A61K 47/26
`C07K 16/24
`A61K 47/10
`A61K 47/12
`A61K 47/02
`A61K 39/00
`(52) vs. C].
`CPC ............. .. A61K 47/26 (2013.01); C07K16/241
`(2013.01); A61K 39/3955 (2013.01); A61K
`47/10 (2013.01); A61K47/12 (2013.01); A61K
`47/02 (2013.01); C07K 2317/94 (2013.01);
`A61K 2039/505 (2013.01)
`USPC ................ .. 424/158.1; 424/130.1; 424/141.1;
`424/145.1; 530/387.1; 530/388.1; 530/388.23;
`530/388.24; 530/399; 530/351
`(58) Field of Classi?cation Search
`CPC ...... .. C07K16/00; C07K16/18; C07K 16/24;
`C07K 16/241; C07K 2316/96; C07K 2317/21;
`
`C07K 2317/56 C07K 2317/56; C07K
`2317/565; C07K 2317/515; C07K 2317/76;
`C07K 2317/94; A61K 39/395; A61K 39/3955;
`A61K 39/39558; A61K 2039/505
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`7/1986 Zolton et a1.
`4,597,966 A
`1/1990 Cordle et a1.
`4,897,465 A
`7/1993 Moeller et al.
`5,231,024 A
`8/1993 Brinks et a1.
`5,237,054 A
`5,358,708 A 10/1994 Patel et a1.
`5,608,038 A
`3/1997 Eibl et a1.
`5,654,403 A
`8/1997 Smith et a1.
`5,792,838 A
`8/1998 Smith et a1.
`5,945,098 A
`8/1999 Sarno et a1.
`5,998,378 A 12/1999 Kreigler et al.
`6,015,557 A
`1/2000 Tobinick et a1.
`6,024,938 A
`2/2000 Corbo et a1.
`6,090,382 A
`7/2000 Salfeld et a1.
`6,165,467 A 12/2000 Hagiwara et a1.
`6,171,586 B1
`1/2001 Lam et a1.
`6,177,077 B1
`1/2001 Tobinick
`6,235,281 B1
`5/2001 Stenzel et a1.
`6,258,562 B1
`7/2001 Salfeld et a1.
`6,267,958 B1
`7/2001 Andya et a1.
`6,379,666 B1
`4/2002 Tobinick
`6,419,934 B1
`7/2002 Tobinick
`6,419,944 B2
`7/2002 Tobinick
`6,423,321 B2
`7/2002 Tobinick
`6,428,787 B1
`8/2002 Tobinick
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`
`0186833
`7/1986
`0218868
`4/1987
`(Continued)
`OTHER PUBLICATIONS
`
`Adalimumab entry from National Library of Medicine website:
`www.nlm.nih.g0v/cgi/mesh; printed on Sep. 28, 2009.
`Akers et al., “Development and Manufacture of Protein Pharmaceu
`ticals (Pharmaceutical Biotechnology)”, Chapter 2: “Formulation
`Development of Protein Dosage Forms”, Kluver Academic/Plenum,
`pub., New York, v01. 14: 47-127 (2002).
`Antoni et al., “Side effects of anti-TNF therapy: Current knowledge,”
`Clinical and Experimental Rheumatology, 20(suppl. 28):S-152-S
`157 (2002).
`Arend et al., “Inhibition of the production and effects of interleukin-1
`and tumor necrosis factor alpha in rheumatoid arthritis,” Arthritis &
`Rheumatism, 38(2):151-l60 (1995).
`(Continued)
`
`Primary Examiner * Bridget E Bunner
`(74) Attorney, Agent, or Firm * Ropes & Gray LLP; James
`F. Haley, Jr.; Z. Ying Li
`
`ABSTRACT
`(57)
`A liquid aqueous pharmaceutical formulation is described
`which has a high protein concentration, a pH of between
`about 4 and about 8, and enhanced stability.
`
`30 Claims, No Drawings
`
`Ex. 1001 - Page 1 of 25
`
`AMGEN INC.
`Exhibit 1001
`
`

`

`US 8,916,158 B2
`Page 2
`
`(56)
`
`References Cited
`
`U_S_ PATENT DQCUMENTS
`
`11/2002 Hirao et al‘
`6,485,725 B1
`11/2002 Mclnosh et al‘
`6,485,932 B1
`100% Salfeld et 31‘
`6,509,015 B1
`5/2004 Roemisch et al‘
`6,737,405 B2
`6,818,613 B2 11/2004 Shanna et al‘
`6,875,432 B2
`4/2005 Liu et 31‘
`7,070,775 B2
`7/2006 Le et al‘
`7,141,542 B2 11/2006 Cowan et al‘
`7,220,409 B2
`5/2007 Norman et 31‘
`7,223,394 B2
`5/2007 Salfeld et 31‘
`7,250,165 B2
`7/2007 Heavner et al‘
`7,276,239 B2 10/2007 Le et al‘
`7,318,931 B2
`1/2008 Okumu et 31‘
`7,541,031 B2
`6/2009 Salfeld et al‘
`7,588,761 B2
`9/2009 Salfeld et al‘
`7,820,651 B2 10/2010 Herdeis et al‘
`7,363,426 B2
`1/2011 wan et 31,
`7,919,264 B2
`4/2011 Maksymowych et al,
`8,821,865 B2 *
`9/2014 Neu et a1. ................. .. 424/130.1
`2001/0004456 A1
`6/2001 Tobinick
`2001/0016195 A1
`8/2001 Tob1n1ck
`2001/0026801 A1 10/2001 Toblnlck
`2003/0012786 A1
`1/2003 Teoh et a1.
`
`
`
`2003/0049725 A1 2003/0138417 A1
`
`
`
`3/2003 Heavner et a1. 7/2003 Kaisheva et a1.
`
`2003/0190316 A1 10/2003 Kakuta et a1.
`
`2003/0235585 A1 12/2003 Fischkoff et a1.
`2004/0009172 A1
`1/2004 Flschkoff et a1.
`
`2004/0126372 A1
`
`7/2004 Banerjee et a1.
`
`6/2009 Fraunhofer et a1.
`2009/0148513 A1
`6/2009 Salfeld et a1.
`2009/0155205 A1
`9/2009 Lassner et a1.
`2009/0226530 A1
`9/2009 Hsieh et :11.
`2009/0239259 A1
`2009/0258018 A1 10/2009 Medich et a1.
`2009/0271164 A1 10/2009 Peng et a1.
`2009/0280065 A1 11/2009 William et a1.
`2009/0291062 A1 11/2009 Fraunhofer et a1.
`2009/0304682 A1 12/2009 Hoffman et a1.
`2009/0317399 A1 12/2009 Pollack et a1.
`2010/0003243 A1
`1/2010 Okun et a1.
`2010/0016557 A1
`1/2010 Salfeld et a1.
`2010/0021451 A1
`1/2010 Wong e_t al.
`2010/0034823 A1
`2/2010 Boihani et a1.
`2010/0040604 A1
`2/2010 Salfeld et al.
`2010/0040630 A1
`2/2010 Elden et al.
`2010/0160894 A1
`6/2010 Jnlian et a1.
`2010/0278822 A1 11/2010 Fraunhofer et a1.
`2011/0002935 A1
`1/2011 Wan et a1.
`2011/0054414 A1
`3/2011 Shang et a1.
`2011/0171227 A1
`7/2011 Okun et a1.
`2012/0263731 A1 10/2012 Fraunhofer et a1.
`2013/0156760 A1
`6/2013 Fraunhofer et a1.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`
`EP
`
`EP
`EP
`
`EP
`
`0419251
`
`3/199 1
`
`0417191
`
`10/1993
`
`0531539
`1174148
`
`6/1998
`10002
`
`1737450
`
`10007
`
`2004/0136989 A1
`
`7/2004 Banerjee et a1.
`
`W0
`
`WO_9001191
`
`M990
`
`2004/0151722 A1
`2004/0156835 A1
`
`8/2004 Banerjee et a1.
`8/2004 Imoto et a1.
`
`W0
`W0
`
`WO_9211383
`WO_9216221
`
`M992
`10/1992
`
`2004/0219142 A1 11/2004 Banerjee et a1.
`
`W0
`
`WO_9308837
`
`5/1993
`
`2005/0118167 A1
`2005/0214278 A1
`
`6/2005 Okada
`9/2005 Kakuta et a1.
`
`2006/0083741 A1
`2006/0127395 A1
`
`4/2006 Hoffman et a1.
`6/2006 Arvinte et a1.
`
`W0
`W0
`
`W0
`W0
`
`WO_9408609
`WO_9420139
`
`WO_9607429
`WO_9704801
`
`4/1994
`9/1994
`
`M996
`M997
`
`2006/0246073 A1 11/2006 Knight et a1.
`
`W0
`
`WO_9822136
`
`5/1998
`
`2007/0071747 A1
`2007/0081996 A1
`
`3/2007 Hoffman et a1.
`4/2007 Hoffman et a1.
`
`8/2007 Banerjee et a1.
`2007/0202104 A1
`2007/0243185 A1 10/2007 Gombotz et a1.
`
`W0
`W0
`
`W0
`W0
`
`WO_9937329
`WO_0050079
`
`WO_0067798
`WO_0143773
`
`M999
`8/2000
`
`11/2000
`6/2001
`
`2008/0131374 A1
`
`6/2008 Medich et a1.
`
`W0
`
`WO_0160420
`
`8/2001
`
`9/2008 Pia et a1.
`2008/0227136 A1
`2008/0286280 A1 11/2008 Kallmeyer et a1.
`2008/0311043 A1 12/2008 Hoffman et a1.
`2009/0017472 A1
`1/2009 Stuhlmuller et a1.
`2009/0028794 A1
`1/2009 Medich et a1.
`2009/0068172 A1
`3/2009 Kaymakcalan et a1.
`2009/0110679 A1
`4/2009 Li et :11.
`2009/0123378 A1
`5/2009 Wong et :11.
`
`W0
`W0
`W0
`W0
`W0
`WO
`W0
`W0
`
`WO_0230463
`WO_02064166
`WO_02072636
`W0_02096457
`WO_02100330
`wo-03009817
`WO-03039485
`WO-03066681
`
`4/2002
`8/2002
`9/2002
`12/2002
`12/2002
`2/2003
`5/2003
`8/2003
`
`Ex. 1001 - Page 2 of 25
`
`

`

`US 8,916,158 B2
`Page 3
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`WO WO-2004007520
`WO WO-2006138181
`WO WO-2013164837
`WO WO-2014039903
`
`1/2004
`12/2006
`11/2013
`3/2014
`
`OTHER PUBLICATIONS
`Barrera et al., “Effects of treatment with a fully human antitumour
`necrosis factor alpha monoclonal antibody on the local and systemic
`homeostasis of interleukin 1 and TNF alpha in I patients with rheu
`matoid arthritis,” Annals of the Rheumatic Diseases, 60(7):660-669
`(2001).
`Bendtzen et al., “Auto-Antibodies to IL-lct and TNFOL in Normal
`Individuals and in Infectious and Immunoin?ammatory Disorders,”
`The Physiological and Pathological Effects of Cytokines, 10B:447
`452 (1990).
`Bertolini et al., “Stimulation of bone resorption and inhibition of
`bone formation in vitro by human tumour necrosis factors,” Nature,
`319(6053):516-518 (1986).
`Beutler et al., “The biology of cachectin/TNFia primary mediator
`of the host response,” Annual Review of Immunology, 7:625-655
`(1989).
`Beutler et al., “Tumor necrosis, cachexia, shock, and in?ammation: a
`common mediator,” Annual Review of Biochemistry, 57:505-518
`(1988).
`Bird et al., “Single-chain antigen-binding proteins,” Science,
`242(4877):423-426 (1988).
`Boyle et al., “A novel monoclonal human IgM autoantibody which
`binds recombinant human and mouse tumor necrosis factor-alpha,”
`Cell Immunology, 152(2):556-568 (1993).
`Boyle et al., “The BS monoclonal human autoantibody binds to cell
`surface TNF alpha on human lymphoid cells and cell lines and
`appears to recognize a novel epitope,” Cell Immunology, 152(2): 569
`581 (1993).
`Cada et al. “Adalimuma ”, Hospital Pharmacy, 3 8,6 : 568-5 80 (2003).
`Carpenter et al., “Rational Design of Stable Lyophilized Protein
`Formulations: Some Practical Advice” Pharmaceutical Research,
`14(8):969-975 (1997).
`Certi?cate of Amalgamation submitted by Patentee during Opposi
`tion of EP1528933 (Aug. 5, 2003).
`Cleland et al., “A Speci?c Molar Ratio of Stabilizer to Protein is
`Required for Storage Stability of a Lyophilized Monoclonal Anti
`body,” Journal of Pharmaceutical Sciences, 90(3):310-321 (2001).
`Coriolis Pharma Technical Report, “Phase 3: Side by Side Compari
`son of ‘Citrate Formulation’ and ‘Claim Formulation’iStability
`Study” (Jan. 10, 2014), submitted by Patentee during Opposition of
`EP1528933.
`Corrected Sequence Listing ?led Feb. 16, 2005 in US Patent
`8,216,583 submitted during Opposition of EP1528933.
`Davis et al., “Structure of human tumor necrosis factor alpha derived
`from recombinant DNA”, Biochemistry, 26(5): 1322-1326 (1987).
`Decision to Refuse Application submitted during Opposition of
`EP1528933 (Dec. 20, 2010).
`De?nitions of “phosphate buffer” and “citrate buffer” according to
`Wikipedia (downloaded Dec. 20, 2012).
`den Broeder et al. Long term anti-tumour necrosis factor a
`monotherapy in rheumatoid arthritis: effect on radiological course
`and prognostic value of markers of cartilage turnover and endothelial
`activation, Annals ofthe Rheumatic Diseases, 61:311-318 (2002).
`Eason et al., “Inhibition of the effects of TNF in renal allograft
`recipients using recombinant human dimeric tumor necrosis factor
`receptors,” Transplantation, 59(2):300-305 (1995).
`Elliot et al., “Randomised double-blind comparison of chimeric
`monoclonal antibody to tumour necrosis factor alpha (cA2) versus
`placebo in rheumatoid arthritis,” Lancet, 344(8930):1105-1110
`(1994).
`Elliott, “Repeated therapy with monoclonal antibody to tumour
`necrosis factor alpha (cA2) in patients with rheumatoid arthritis,”
`Lancet, 344(8930):1125-1127 (1994).
`
`Ewert et al., “Biophysical properties of human antibody variable
`domains,” Journal of Molecular Biology, 325(3):531-553 (2003).
`Expert Opinion of Professor Gerhard Winter (Jan. 13, 2014), submit
`ted by Patentee during Opposition of EP1528933.
`Fava et al., “Critical role of peripheral blood phagocytes and the
`involvement of complement in tumour necrosis factor enhancement
`of passive collagen-arthritis,” Clinical and Experimental Immunol
`ogy, 94(2):261-266 (1993).
`Felver et al., “Plasma tumor necrosis factor alpha predicts decreased
`long-term survival in severe alcoholic hepatitis,” Alcoholism, Clini
`cal and Experimental Research, 14(2):255-259 (1990).
`Fendly et al., “Murine monoclonal antibodies de?ning neutralizing
`epitopes on tumor necrosis factor,” Hybridoma, 6(4):359-370 (1987).
`Fiedler: “Encyclopedia of Excipients,” Editio Cantor Verlag
`Aulendorf, 5th Edition, 2002, Tween® entry.
`Fiedler: ’Lexikon der Hifsstoffe’, 1996, Editio Cantor Verlag
`Aulendorf.
`Fietze et a1 ., “Cytomegalovirus infection in transplant recipients. The
`role of tumor necrosis factor,” Transplantation, 58(6):675-680
`(1994).
`Fomsgaard et al., “Auto-antibodies to tumour necrosis factor alpha in
`healthy humans and patients with in?ammatory diseases and gram
`negative bacterial infections,” Scandinavian Journal of Immunology,
`30(2):219-223 (1989).
`Giroir et al., “Inhibition of tumor necrosis factor prevents myocardial
`dysfunction during burn shock,” American Journal of Physiology,
`267(1 Pt 2):H118-H124 (1994).
`Grif?ths et al., “Human anti-self antibodies with high speci?city
`from phage display libraries,” EMBO Journal, 12(2):725-734 (1993).
`Grounds of Appeal ?led by Applicant submitted during Opposition of
`EP1528933 (Apr. 29, 2011).
`Hahn et al., “Use of monoclonal antibodies to a human cytotoxin for
`its isolation and for examining the self-induction of resistance to this
`protein,” PNAS, 82(11):3814-3818 (1985).
`Hansen et al., “The role of tumor necrosis factor-alpha in acute
`endotoxin-induced hepatotoxicity in ethanol-fed rats,” Hepatology,
`20(2):461-474 (1994).
`Harris et al., “Commercial manufacturing scale formulation and ana
`lytical characterization of therapeutic recombinant antibodies”, Drug
`Development Research, 61(3): 137-154 (2004).
`Helms et al., “Destabilizing loop swaps in the CDRs of an
`immunoglobulin VL domain,” Protein Science, 4(10):2073-2081
`(1995).
`Hillgren et al., “Protection mechanism of Tween 80 during freeze
`thawing of a model protein,” International Journal of Pharmaceutics,
`237:57-69 (2002).
`Hirai et al., “Production and characterization of monoclonal antibod
`ies to human tumor necrosis factor,” Journal of Immunological Meth
`ods, 96(1):57-62 (1987).
`Holliger et al., ““Diabodies”: small bivalent and bispeci?c antibody
`fragments,” PNAS, 90(14):6444-6448 (1993).
`Holt et al., “Domain antibodies: proteins for therapy,” Trends in
`Immunology, 21(11 ):484-490 (2003).
`Hovgaard & Frokjaer (eds) “Pharmaceutical Formulation Develop
`ment of Peptides and Proteins”, CRC Press 1999.
`Humira (adalimumab) Product Insert, Dec. 20, 2002 (16 pages).
`Hussain et al., “Hepatic expression of tumour necrosis factor-alpha in
`chronic hepatitis B virus infection,” Journal of Clinical Pathology,
`47(12): 1 1 12-1 1 15 (1994).
`Huston et al., “Protein engineering of antibody binding sites: recov
`ery of speci?c activity in an anti-digoxin single-chain Fv analogue
`produced in Escherichia coli,” PNAS, 85(16):5879-5883 (1988).
`International Preliminary Examination Report for Application No.
`PCT/IB03/04502, dated Feb. 14, 2005.
`International Search Report for Application No. PCT/IB03/04502
`dated May 26, 2004.
`Johnsson et al., “Comparison of methods for immobilization to
`carboxymethyl dextran sensor surfaces by analysis of the speci?c
`activity of monoclonal antibodies,” Journal of Molecular Recogni
`tion, 8(1-2):125-131 (1995).
`a
`to
`of proteins
`Johnsson
`et
`al.,
`“Immobilization
`carboxymethyldextran-modi?ed gold surface for bio speci?c interac
`
`Ex. 1001 - Page 3 of 25
`
`

`

`US 8,916,158 B2
`Page 4
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`tion analysis in surface plasmon resonance sensors,” Analytical Bio
`chemistry, 198(2):268-277 (1991).
`Jones et al., “Analysis of polypeptides and proteins,” Advanced Drug
`Delivery Reviews, 10:29-90 (1993).
`Jones et al., “Structure of tumour necrosis factor,” Nature,
`338(6212):225-228 (1989).
`Jonsson et al., “Introducing a biosensor based technology for real
`time biospeci?c interaction analysis,” Annales de Biologie Clinque
`(Paris), 51(1):19-26 (1993).
`Jonsson et al., “Real-time biospeci?c interaction analysis using sur
`face plasmon resonance and a sensor chip technology,”
`Biotechniques, 11(5):620-627 (1991).
`Kempeni, “Update on D2E7: a fully human anti-tumor necrosis fac
`tor a Monoclonal antibody,” Annals of the Rheumatic Diseases,
`59(suppl I):i44-i45 (2000).
`Kipriyanov et al., “Recombinant single-chain Fv fragments carrying
`C-terminal cysteine residues: production of bivalent and biotinylated
`miniantibodies,” Molecular Immunology, 31(14):1047-1058
`F(1994).
`Kipriyanov et al., “Single-chain antibody streptavidin fusions:
`tetrameric bifunctional scFv-complexes with biotin binding activity
`and enhanced af?nity to antigen,” Human Antibodies and
`Hybridomas, 6(3):93-101 (1995).
`Knight et al., “Construction and initial characterization of a mouse
`human chimeric anti-TNF antibody,” Molecular Immunology,
`30(16):1443-1453 (1993).
`Konig et a1 ., “Tumor necrosis factor alpha and interleukin-1 stimulate
`bone resorption in vivo as measured by urinary [3H]tetracycline
`excretion from prelabeled mice,” Journal of Bone and Mineral
`Research, 3(6):621-627 (1988).
`Lerner et al., “Tumor necrosis factors alpha and beta can stimulate
`bone resorption in cultured mouse calvariae by a prostaglandin
`independent mechanism,” Journal of Bone and Mineral Research,
`8(2):147-155(1993).
`Leusch et al., “Failure to demonstrate TNF alpha-speci?c
`autoantibodies in human sera by ELI SA and western blot,” Journal of
`Immunological Methods, 139(1):145-147 (1991).
`Liang et al., “Production and characterization of monoclonal anti
`bodies against recombinant human tumor necrosis factor/cachectin,”
`Biochemical and Biophysical Research Communications,
`137(2):847-854 (1986).
`Lidbury et al., “The effect of enhancing antibodies on TNF interac
`tions with its speci?c receptor: consequences for in vitro TNF anti
`viral activity,” Biotechnology Therapies, 5(1&2):27-45 (1994).
`Liu et al., “The signi?cance of changes in serum tumour necrosis
`factor (TNF) activity in severely burned patients,” Burns, 20(1):40
`44 (1994).
`MacDonald et al., “Tumour necrosis factor-alpha and interferon
`gamma production measured at the single cell level in normal and
`in?amed human intestine,” Clinical and Experimental Immunology,
`81(2):301-305 (1990).
`McCauley et al., “Altered cytokine production in black patients with
`keloids,” Journal of Clinical Immunology, 12(4):300-308 (1992).
`McClain et al., “Increased tumor necrosis factor production by
`monocytes in alcoholic hepatitis,” Hepatology, 9(3):349-351 (1989).
`Moeller et al., “Monoclonal antibodies to human tumor necrosis
`factor alpha: in vitro and in vivo application,” Cytokine, 2(3): 162-169
`(1990).
`Notice of opposition of European Patent EP1528933, submitted by
`Alfred E. Tiefenbacher, Feb. 1, 2013 (with English Translation).
`Notice of opposition of European Patent EP1528933, submitted by
`Dr. Ulrich Storz, Feb. 1, 2013.
`Notice of opposition of European Patent EP1528933, submitted by
`Teva Pharmaceutical Industries Ltd., Feb. 4, 2013.
`Notice of opposition of European Patent EP1528933, submitted by
`William Edward Bird, Jan. 31, 2013.
`Old, “Tumor necrosis factor (TNF),” Science, 230(4726):630-632
`(1985).
`
`Paborij et al., “Chemical and Physical Stability of Chimeric L6, a
`Mouse-Human Monoclonal Antibody,” Pharmaceutical Research,
`11, 5:764-771 (1994).
`Patentee Priority Application Assignment in US. Appl. No.
`10/222,140 submitted during Opposition of EP1528933 (Dec. 12,
`2002).
`Patentee’s Compilation Record submitted during Opposition of
`EP1528933 (Jan. 10, 2014).
`Patentee’s Recordation of Name Change in PCT/IB2003/004502
`submitted by Patentee during Opposition of EP1528933 (Jan. 18,
`2005).
`Patentee’ s Request for Name Change submitted during Opposition of
`EP1528933 (Dec. 1,2005).
`Patentee’s Response on 71(3 ) Communication submitted during
`Opposition of EP1528933, plus Request to Correct the Sequence
`Listing (Feb. 15, 2012).
`Patentee’s Response submitted during Oppositions of EP1528933
`(Jan. 17,2014).
`PBS recipe as published by Cold Spring Harbor Protocols (down
`loaded Dec. 19, 2012).
`Pearlman et al., “Analysis of Protein Drugs,” Peptide and Protein
`Drug Delivery, Marcel Dekker, Inc., pp. 247-301 (1991).
`Pennica et al., “Human tumour necrosis factor: precursor structure,
`expression and homology to lymphotoxin,” Nature, 312(5996):724
`729 (1984).
`Pennington et al., “Polyclonal and monoclonal antibody therapy for
`experimental Pseudomonas aeruginosa pneumonia”, Infection and
`Immunity, 54(1):239-244 (1986).
`Perchiacca et al., “Engineering Aggregation Resistant Antibodies,”
`Annual Review of Chemical and Biomolecular Engineering, 3:263
`286 (2012).
`Polj ak, “Production and structure of diabodies,” Structure,
`2(12):1121-1123 (1994).
`Product Information Issued by the European Medicines Agency
`(EMA) with Respect to adalimumab/Humira® -EMENH/C/
`000481-II/0094, Aug. 2012 (212 pages).
`Rankin et al., “The therapeutic effects of an engineered human anti
`tumour necrosis factor alpha antibody (CDP571) in rheumatoid
`arthritis,” British Journal of Rheumatology, 34(4):334-342 (1995).
`Rau, “Adalimumab (a fully human anti -tumour necrosis factor alpha
`monoclonal antibody) in the treatment of active rheumatoid arthritis:
`the initial results of ?ve trials,” Annals of Rheumatic Disease,
`61(Suppl II):ii70-ii73 (2002).
`Register Extract of US. Appl. No. 10/222,140 submitted during
`Opposition of EP1528933 (downloaded Dec. 7, 2012).
`Result of Consultation of Oct. 28, 2010 by the EPO submitted during
`Opposition of EP1528933 (Nov. 3, 2010).
`Russel et al., “Targets for sepsis therapies: tumor necrosis factor
`versus interleukin-1,” Current Opinion in Biotechnology, 4:714-721
`(1993).
`Salfeld, “Generation of Fully Human Anti-TNF Antibody D2E7,”
`Arthritis and Rheumatism, 41(9):S57, Abstract 147 (1998).
`Scales et al., “Hepatic ischemia/reperfusion injury: importance of
`oxidant/tumor necrosis factor interactions,” American Journal of
`Physiology, 267(6 Pt 1):G1122-G1127 (1994).
`Sequence Listing ?led with US. Appl. No. 10/222,140 submitted
`during Opposition of EP1528933 (May 6, 2003).
`Serrick et al., “The early release of interleukin-2, tumor necrosis
`factor-alpha and interferon-gamma after ischemia reperfusion injury
`in the lung allograft,” Transplantation, 58(11):1158-1162 (1994).
`Shankar et al., “Evaluation of the role of second messenger systems
`in tumor necrosis factor-stimulated resorption of fetal rat limb
`bones,” Bone, 14(6):871-876 (1993).
`Sheron et al., “Increased production of tumour necrosis factor alpha
`in chronic hepatitis B virus infection,” Journal of Hepatology,
`12(2):241-245 (1991).
`Shimazato et al., “Suppression of Tumor Necrosis Factor Alpha
`Production by a Human Immuno globulin Preparation for Intravenous
`Use”, Infection and Immunity, 58: 1384-1390 (1990).
`Sivasai et al., “Cytomegalovirus immune globulin intravenous
`(human) administration modulates immune response to alloantigens
`in sensitized renal transplant candidates”, Clinical & Experimental
`Immunology, 119:559-565 (2000).
`
`Ex. 1001 - Page 4 of 25
`
`

`

`US 8,916,158 B2
`Page 5
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Summons to Oral Proceedings with Annex submitted during Oppo
`sition of EP1528933 (Apr. 6, 2010).
`Sun et al., “Bowel necrosis induced by tumor necrosis factor in rats is
`mediated by platelet-activating factor,” Journal of Clinical Investiga
`tion, 81(5): 1328-1331 (1998).
`Suthanthiran et al., “Renal Transplantation,” New England Journal of
`Medicine, 33 l(6):365-375 (1994).
`Taylor et a1 ., “A transgenic mouse that expresses a diversity of human
`sequence heavy and light chain immunoglobulins,” Nucleic Acids
`Research, 20(23):6287-6295 (1992).
`Test Report as cited during prosecution of related European Patent
`No. EP1528933, grant date of Sep. 28, 2012 (27 pages).
`Third Party Observations submitted during Opposition of
`EP1528933 (Aug. 26, 2011).
`Tracey et al., “Shock and tissue injury induced by recombinant
`human cachectin,” Science, 234(4775):470-474 (1986).
`Tracey et al., “Tumor necrosis factor: a pleiotropic cytokine and
`therapeutic target,” Annual Review of Medicine, 45:491-503 (1994).
`Van Der Poll et al., “Activation of coagulation after administration of
`tumor necrosis factor to normal subjects,” New England Journal of
`Medicine, 322(23):l622-l627 (1990).
`Van Der Poll et a1 ., “Comparison of the early dynamics of coagulation
`activation after injection of endotoxin and tumor necrosis factor in
`healthy humans,” Progress in Clinical and Biological Research,
`367:55-60 (1991).
`Van Dullemen et al., “Treatment of Crohn’s disease with anti -tumor
`necrosis factor chimeric monoclonal antibody (cA2),” Gastroenter
`ology, 109(1):l29-l35 (1995).
`
`Vassalli, “The pathophysiology of tumor necrosis factors,” Annual
`Review of Immunology, 10:4ll-452 (1992).
`Voigt et al., “Textbook of Pharmaceutical Technology,” VCH, pp.
`384, 385, 388, 389, 392, 393 (1987).
`Wang et al. “Instability, Stabilization, and Formulation of Liquid
`Protein Pharmaceuticals,” International Journal of Pharmaceutics,
`185:129-188 (1999).
`Wang et al., “Antibody Structure, Instability, and Formulation,” Jour
`nal of Pharmaceutical Sciences, 96(1): 1-26 (2007).
`Wang, “Lyophilization and development of solid protein pharmaceu
`ticals,” International Journal of Pharmaceutics, I(203), l-2:l-60
`(2000).
`Ward et al., “Binding activities of a repertoire of single
`immunoglobulin variable domains secreted from Escherichia coli,”
`Nature, 34l(6242):544-546 (1989).
`Weinblatt et al., “Adalimumab, a fully human anti-tumor necrosis
`factor alpha monoclonal antibody, for the treatment of rheumatoid
`arthritis in patients taking concomitant methotrexate: the ARMADA
`trial,” Arthritis and Rheumatism, 48(1):35-45 (2003).
`Yao et al., “The potential etiologic role of tumor necrosis factor in
`mediating multiple organ dysfunction in rats following intestinal
`ischemia-reperfusion injury,” Resuscitation, 29(2): 157-168(1995).
`Zhao et al., “Recent US. Patents on Protein Drug Formulation:
`2000-2007,” Recent Patents on Drug Delivery and Formulation,
`2(3):200-208(9) (2008).
`Mithal, “A Textbook of Pharmaceutical Formulation: Surfactants, the
`Interfacial Phenomenon,” Chapter 6, pp. 49-62 , Oct. 9, 1980.
`
`* cited by examiner
`
`Ex. 1001 - Page 5 of 25
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`

`

`US 8,916,158 B2
`
`1
`FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-(x ASSOCIATED
`DISORDERS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of US. patent applica
`tion Ser. No. 14/322,581, ?led Jul. 2, 2014 (now pending),
`which is continuation of US. patent application Ser. No.
`14/091,938, ?led Nov. 27, 2013, now US. Pat. No. 8,795,
`670, issued Aug. 5, 2014, which is a continuation of US.
`patent application Ser. No. 13/471,820, ?led May 15, 2012
`(now pending), which is a continuation of US. patent appli
`cation Ser. No. 10/525,292 ?led Oct. 27, 2005, now US. Pat.
`No. 8,216,583, issued Jul. 10, 2012, which is a United States
`National Stage Application under 35 U.S.C. §371 of PCT/
`IB2003/004502, ?led Aug. 15, 2003 (now expired), which is
`a continuation of US. patent application Ser. No. 10/222, 140,
`?led Aug. 16, 2002 (now abandoned). Each of these applica
`tions is herein incorporated by reference in its entirety.
`
`20
`
`SEQUENCE LISTING
`
`The Sequence Listing associated with this application is
`provided in text format in lieu of a paper copy, and is hereby
`incorporated by reference into the speci?cation. The name of
`the text ?le containing the Sequence Listing is 1 10222-0005
`310-SL.txt. The text ?le is 11,377 bytes in size, was created
`on Aug. 6, 2014, and is being submitted electronically via
`EFS Web.
`
`25
`
`30
`
`BACKGROUND OF THE INVENTION
`
`Tumor necrosis factor 0t (TNFG) is a cytokine produced by
`numerous cell types, including monocytes and macrophages,
`that was originally identi?ed based on its capacity to induce
`the necrosis of certain mouse tumors (see e.g., Old, L. (1985)
`Science 230: 630-632). Subsequently, a factor termed cachec
`tin, associated with cachexia, was shown to be the same
`molecule as TNFG. TNFO. has been implicated in mediating
`shock (see e.g., Beutler, B. and Cerami, A. (1988)Annu. Rev.
`Biochem. 57:505-518; Beutler, B. and Cerami, A. (1989)
`Annu. Rev. Immunol. 7:625-655). Furthermore, TNFO. has
`been implicated in the pathophysiology of a variety of other
`human diseases and disorders, including sepsis, infections,
`autoimmune diseases, transplant rejection and graft-versus
`host disease (see e.g., Moeller, A., et al. (1990) Cytokine
`2:162-169; US. Pat. No. 5,231,024 to Moeller et al.; Euro
`pean Patent Publication No. 260 610 B1 by Moeller, A., et al.
`Vasilli, P. (1992)Annu. Rev. Immunol. 10:41 1-452; Tracey, K.
`J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503).
`Because of the harmful role of human TNFO. (hTNFa) in a
`variety of human disorders, therapeutic strategies have been
`designed to inhibit or counteract hTNFa activity. In particu
`lar, antibodies that bind to, and neutralize, hTNFa have been
`sought as a means to inhibit hTNFa activity. Some of the
`earliest of such antibodies were mouse monoclonal antibod
`ies (mAbs), secreted by hybridomas prepared from lympho
`cytes of mice immunized with hTNFa (see e.g., Hahn T; et al.,
`(1985) Proc NatlAcadSci USA 82: 3814-3818; Liang, C-M.,
`et al. (1986) Biochem. Biophys. Res. Commun. 137:847-854;
`Hirai, M., et al. (1987) J. Immunol. Methods 96:57-62;
`Fendly, B. M., et al. (1987) Hybridoma 6:359-370; Moeller,
`A., et al. (1990) Cytokine 2: 162-169; US. Pat. No. 5,231,024
`to Moeller et al.; European Patent Publication No. 186 833 B1
`by Wallach, D.; European Patent Application Publication No.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`218 868 A1 by Old et al.; European Patent Publication No.
`260 610 B1 by Moeller, A., et al.). While these mouse anti
`hTNFa antibodies often displayed high af?nity for hTNFa
`(e.g., Kd510_9M) and were able to neutralize hTNFa activity,
`their use in vivo may be limited by problems associated with
`administration of mouse antibodies to humans, such as short
`serum half life, an inability to trigger certain human effector
`functions and elicitation of an unwanted immune response
`against the mouse antibody in a human (the “human anti
`mouse antibody” (HAMA) reaction).
`In an attempt to overcome the problems associated with use
`of fully-murine antibodies in humans, murine anti-hTNFa
`antibodies have been genetically engineered to be more
`“human-like.” For example, chimeric antibodies, in which the
`variable regions of the antibody chains are murine-derived
`and the constant regions of the antibody chains are human
`derived, have been prepared (Knight, D. M, et al. (1993)Mol.
`Immunol. 30: 1443-1453; PCT Publication No. WO 92/16553
`by Daddona, P. E., et al.). Additionally, humanized antibod
`ies, in which the hypervariable domains of the antibody vari
`able regions are murine-derived but the remainder of the
`variable regions and the antibody constant regions are
`human-derived, have also been prepared (PCT Publication
`No. WO 92/11383 by Adair, J. R., et al.). However, because
`these chimeric and humanized antibodies still retain some
`murine sequences, they still may elicit an unwanted immune
`reaction, the human anti-chimeric antibody (HACA) reac
`tion, especially when administered for prolonged periods,
`e.g., for chronic indications, such as rheumatoid arthritis (see
`e.g., Elliott, M. J., etal. (1994)Lancet344:1 125-1127; Elliot,
`M. J., et al. (1994) Lancet 344:1105-1110).
`A preferred llTNFU. inhibitory agent to murine mAbs or
`derivatives thereof (e.g., chimeric or humanized antibodies)
`would be an entirely human anti-hTNFa antibody, since such
`an agent should not elicit the HAMA reaction, even if used for
`prolonged periods. Human monoclonal autoantibodies
`against hTNFa have been prepared using human hybridoma
`techniques (Boyle, P., et al. (1993) Cell. Immunol. 152:556
`568; Boyle, P., et al. (1993) Cell. Immunol. 152:569-581;
`European Patent Application Publication No. 614 984 A2 by
`Boyle, et al.). However, these hybridoma-derived mono
`clonal autoantibodies were reported to have an af?nity for
`hTNFa that was too low to calculate by conventional meth
`ods, were unable to bind soluble hTNFa and were unable to
`neutralize hTNFa-induced cytotoxicity (see Boyle, et al.;
`supra). Moreover, the success of the human hybridoma tech
`nique depends upon